Effects of cholinergic and monoaminergic antagonists and tranquilizers upon spatial memory in rats

To explore the pharmacological mechanisms of the spatial memory, performance on the radial arm maze was tested in rats under the following drugs, using a within-subject design; scopolamine (0.25 and 0.5 mg/kg), methylscopolamine (0.5 and 1 mg/kg), phentolamine (5 and 10 mg/kg), propranolol (10 and 20 mg/kg), chlorpromazine (1 and 2 mg/kg), and chlordiazepoxide (5 and 10 mg/kg). The number of correct choices was significantly decreased by scopolamine, while the other drugs, including methylscopolamine, showed no effects on the correct choices. Almost all drugs affected the running time. These findings indicate that the brain cholinergic system is involved in the spatial memory.     

Differential effects of iloperidone,clozapine, and haloperidol on working memory of rats in the delayed non-matching-to-position paradigm

Rationale Because cognitive function, particularly working memory (WM), is severely impaired in schizophrenia, evaluation of neuroleptic medication should include investigation of possible effects on cognition. Iloperidone is a promising, novel atypical neuroleptic drug (NL), for which no cognitive data is presently available.Objective To investigate whether the novel atypical NL iloperidone would affect performance of rats on a WM test, using a delayed non-matching-to-position (DNMTP) paradigm, and compare its effects with those of the atypical NL clozapine and the typical NL haloperidol.Methods Male Lister Hooded rats trained to criterion in an operant DNMTP task (0–64 s delay intervals) were administered vehicle, iloperidone (0.03, 0.1 mg/kg, i.p.), clozapine (0.1, 0.3 mg/kg, s.c.), haloperidol (0.003, 0.01, 0.03 mg/kg, s.c.), or scopolamine (0.05 mg/kg, s.c.). Together with choice accuracy, the motor performance of the task was measured.Results It was found that: (1) iloperidone significantly improved choice accuracy delay-dependently while impairing task performance; (2) the atypical NL clozapine had no effect on choice accuracy and parameters related to motor function, but significantly increased the number of uncompleted trials; (3) haloperidol did not affect choice accuracy except at the longest delay with the highest dose, but in contrast to clozapine it significantly impaired task performance.Conclusion In accordance with their different pharmacological profiles, the three NLs iloperidone, clozapine, and haloperidol have different effects in this preclinical cognitive task. These results might provide important information for the development of NLs with beneficial effects on cognition.     

Pharmacological manipulation of human working memory

Rationale The goal of this paper is to briefly overview human studies that have examined pharmacological agents designed to enhance working memory function, with the idea of providing clues as to promising avenues to follow for the development of drugs likely to enhance working memory and other cognitive processes in individuals with schizophrenia.Objectives We reviewed the studies that have used pharmacological agents designed to target the dopamine system, the noradrenergic system, the acetycholine system, the serotonin system, and the glycine site on NMDA receptors.Results There are a large number of studies suggesting that dopamine agents can enhance working memory, though there remain conflicting issues regarding the role that baseline performance plays in modulating the influence of drug and the importance of different dopamine receptors. There is also consistent evidence that cholinesterase inhibitors can enhance working memory function, potentially through improved encoding of the information. There is less consistent evidence that noradrenergic alpha-2 agonists consistently improve working memory in humans, despite the large animal literature suggesting that these agents should have a beneficial effect on memory. As of yet, there is little evidence that agents targeting the glycine site of the NMDA receptor improve working memory, and data to suggest that enhancement of the serotonin system impairs working memory.Conclusions Compounds geared towards enhancing the dopamine system and the acetycholine system remain promising avenues for the development of pro-cognitive drugs, though further work is clearly needed on developing agents that may more selectively target specific receptors.     

Opiate antagonists, morphine and spatial memory in rats

To assess the possible role of endogenous opioids on spatial memory, rats were administered morphine (1-15 mg/kg), naloxone (1-10 mg/kg), or naltrexone (0.1-10 mg/kg) at varying times after or prior to completing the first 4 choices in an 8 arm radial maze. None of these agents consistently affected retention, suggesting that endogenous opioid systems do not play a major role in modulating neural mechanisms that maintain accurate spatial memory.     

Scopolamine does not disrupt spatial working memory in rats

The importance of cholinergic systems for spatial working memory was examined by injecting scopolamine at varying times during a 5 hr-long retention interval imposed between the rat's fourth and fifth choices in an 8 arm maze. Regardless of whether or not the testing procedure required the rats to adopt a spatial solution for the task, scopolamine (1.0–5.0 mg/kg) did not impair retention in a manner that was suggestive of an effect on working memory. Modest deficits observed in some conditions appeared to result from drug effects on performance. Previous findings of impaired acquisition of accurate spatial behavior by scopolamine-treated rats evidently reflect an influence of the drug on physiological systems other than those necessary to maintain working memory for spatial information.     

Propranolol blocks chronic risperidone treatment-induced enhancement of spatial working memory performance of rats in a delayed matching-to-place water maze task

Rationale Atypical antipsychotics improve cognitive function, including working memory, in schizophrenia. Some atypical antipsychotics have been reported to activate the locus coeruleus and induce beta-adrenoceptor antagonist sensitive c-Fos-like immunoreactivity in the prefrontal cortex. Materials and methods The present study investigated the effects of chronic treatment of rats with risperidone (1 mg kg⁻¹ day⁻¹ s.c.), clozapine (10 mg kg⁻¹ day⁻¹ s.c.), or acidified saline vehicle control for 2, 4, or 8 weeks on spatial working memory performance in a delayed matching-to-place water maze task with a 60-s inter-trial retention interval with and without acute challenge with propranolol (10 mg/kg i.p.). Results Treatment with risperidone for 8 weeks, but not 2 or 4 weeks, significantly improved working memory performance. In contrast, treatment with clozapine for up to 8 weeks did not improve working memory. Acute challenge with propranolol blocked the improvement in working memory produced by chronic treatment with risperidone, but had no significant effect on performance in saline- or clozapine-treated animals. Conclusions The delayed matching-to-place water maze task may prove valuable in the investigation of the behavioural pharmacology of the cognitive effects of antipsychotic drugs. These data suggest that beta adrenoceptors may contribute to the cognitive effects of chronic treatment with atypical antipsychotics.     

Differential effects of scopolamine on working and reference memory of rats in the radial maze

Anticholinergics have often been found to impair choice accuracy in the radial maze. Some researchers have suggested that this indicates involvement of cholinergically innervated structures in cognitive mapping while others argue that these structures mediate working memory. However, most results are open to either interpretation since the baiting method did not allow a distinction between reference and working memory errors. To further test these hypotheses this study examined the effects of systemic scopolamine on radial maze performance, using a 4-out-of-8 baiting procedure. Food-deprived Wistar rats were pretrained until working memory choice accuracy stabilized to a criterion of 87% or better. Scopolamine (0.1, 0.4 and 0.8 mg/kg, IP, 30 min before a session) significantly increased the number of working memory errors (re-entries into baited arms) whereas reference memory errors (entries into never baited arms) did not change significantly. Observed deficits appeared not to be attributable to a drug-induced disruption of motivational systems. Results confirm the behavioural similarities between the memorial effects of hippocampectomy and anticholinergics, and implicate cholinergically innervated structures in working memory.     

Differential effects of THC- or CBD-rich cannabis extracts on working memory in rats

Cannabinoid receptors in the brain (CB₁) take part in modulation of learning, and are particularly important for working and short-term memory. Here, we employed a delayed-matching-to-place (DMTP) task in the open-field water maze and examined the effects of cannabis plant extracts rich in either Δ⁹-tetrahydrocannabinol (Δ⁹-THC), or rich in cannabidiol (CBD), on spatial working and short-term memory formation in rats. Δ⁹-THC-rich extracts impaired performance in the memory trial (trial 2) of the DMTP task in a dose-dependent but delay-independent manner. Deficits appeared at doses of 2 or 5 mg/kg (i.p.) at both 30 s and 4 h delays and were similar in severity compared with synthetic Δ⁹-THC. Despite considerable amounts of Δ⁹-THC present, CBD-rich extracts had no effect on spatial working/short-term memory, even at doses of up to 50 mg/kg. When given concomitantly, CBD-rich extracts did not reverse memory deficits of the additional Δ⁹-THC-rich extract. CBD-rich extracts also did not alter Δ⁹-THC-rich extract-induced catalepsy as revealed by the bar test. It appears that spatial working/short-term memory is not sensitive to CBD-rich extracts and that potentiation and antagonism of Δ⁹-THC-induced spatial memory deficits is dependent on the ratio between CBD and Δ⁹-THC.     

Effects of antagonists upon locomotor stimulation induced by injection of dopamine and noradrenaline into the nucleus accumbens of nialamide-pretreated rats

The effects of injections of monoamines, alone and in combination with different antagonists, bilaterally into the nucleus accumbens of nialamide-pretreated rats were investigated.Dopamine was found to produce a stronger stimulation of locomotor activity than noradrenaline, whereas serotonin was effective only in a small number of animals, in which the duration of locomotor stimulation was shorter than after dopamine or noradrenaline. The effects of both dopamine and noradrenaline were completely antagonized by administration of a small dose of the dopamine antagonist haloperidol, administered bilaterally 15 min after the catecholamines. The -adrenergic antagonist phentolamine did not inhibit the effect of noradrenaline but, on the contrary, potentiated and considerably prolonged the duration of locomotor stimulation. Also, the effect of dopamine was potentiated and prolonged by phentolamine. Bilateral injection of phentolamine alone had no influence upon locomotor activity. The effect of noradrenaline was not clearly inhibited nor potentiated by the -adrenergic antagonist propranolol. It is suggested that the stimulation of locomotor activity induced by injection of noradrenaline into the nucleus accumbens of nialamide-pretreated rats is brought about via dopaminergic mechanisms.     

Spatial working memory in heavy cannabis users: a functional magnetic resonance imaging study

Rationale Many neuropsychological studies have documented deficits in working memory among recent heavy cannabis users. However, little is known about the effects of cannabis on brain activity.Objective We assessed brain function among recent heavy cannabis users while they performed a working memory task.Methods Functional magnetic resonance imaging was used to examine brain activity in 12 long-term heavy cannabis users, 6–36 h after last use, and in 10 control subjects while they performed a spatial working memory task. Regional brain activation was analyzed and compared using statistical parametric mapping techniques.Results Compared with controls, cannabis users exhibited increased activation of brain regions typically used for spatial working memory tasks (such as prefrontal cortex and anterior cingulate). Users also recruited additional regions not typically used for spatial working memory (such as regions in the basal ganglia). These findings remained essentially unchanged when re-analyzed using subjects ages as a covariate. Brain activation showed little or no significant correlation with subjects years of education, verbal IQ, lifetime episodes of cannabis use, or urinary cannabinoid levels at the time of scanning.Conclusions Recent cannabis users displayed greater and more widespread brain activation than normal subjects when attempting to perform a spatial working memory task. This observation suggests that recent cannabis users may experience subtle neurophysiological deficits, and that they compensate for these deficits by working harder—calling upon additional brain regions to meet the demands of the task.     

Anorexigenic effects of d-amphetamine and 1-dopa in the rat

The effect of amphetamine and 1-dopa was compared in 22-hr food- and water-deprived rats. Amphetamine produced marked anorexia, and 1-dopa significantly reduced food intake at 200 mg/kg. Following pretreatment with RO 4-4602, a decarboxylase inhibitor, 100 mg/kg of 1-dopa, a dose that did not significantly affect eating, produced marked anorexia. The anorectic effect of both amphetamine and 1-dopa was antagonized by propranolol, a β adrenergic antagonist. Phentolamine, an a-adrenergic antagonist, potentiated the anorectic effect of amphetamine and 1-dopa. Haloperidol (0.1 mg/kg), a dopamine antagonist, failed to prevent the anorexia due to amphetamine but accentuated that due to 1-dopa. Methysergide, a serotonin antagonist, also failed to prevent the anorexigenic effect of amphetamine. Finally, the administration of 1-dopa with or without peripheral decarboxylase inhibition resulted in more than twice the increase in hypothalamic dopamine levels without significant changes in 5-HT or norepinephrine levels. The data show that the anorexigenic effect of amphetamine and 1-dopa are similar and indicate a functional role for both norepinephrine and dopamine neurons in feeding behaviour in the rat.     

The effects of scopolamine on working memory in healthy young volunteers

Twenty healthy young adults completed a series of nonverbal and problem solving tasks in a repeated measures design involving placebo and 0.6 mg scopolamine, administered by subcutaneous injection. Subjects completed the test battery under standard presentation conditions and with concurrent articulation, which precludes verbal recoding of test material. Under standard presentation conditions, scopolamine significantly impaired performance on the problem solving task and on tasks of visuo-spatial and spatial memory; memory for abstract shapes was not impaired. Concurrent articulation impaired performance on the shape recognition and interacted with drug treatment on the problem solving task. The results suggest that scopolamine impairs working memory, and that the decrement is at the level of the central executive mechanism rather than the subsystems which it controls.     

Infusions into the oculomotor nucleus or nerve: a method of estimating the dosage at which transmitter antagonists infused intracranially produce nonspecific blocking of neural activity

Lidocaine, a local anesthetic, was first infused into the oculomotor nucleus or nerve in anesthetized rats through one barrel of a two barrel infusion needle and the extent of pupillary dilation measured. Ten to fifteen minutes after the pupillary diameter had returned to its preinfusion level, a transmitter antagonist was injected through the second barrel of the cannula and its effect on pupillary diameter measured. Lidocaine, when in close proximity to the oculomotor nucleus or nerve produced a dilation of 3 to 4 mm while saline produced no consistent change. Infusion of phentolamine (α-adrenergic), tolazoline (α-adrenergic), atropine (cholinergic), and haloperidol (dopaminergic) but not propranolol (β-adrenergic) produced increases in pupillary diameter as large as those produced by lidocaine whether infused along the nerve or into the nucleus. In a second experiment using unanesthetized rats, dilation by each of these substances and infusion methyl nitrate and propranolol induced dilation when infused into the oculomotor nucleus. In a final experiment, (dopamine) agonists produced pupillary constriction. These results suggest that pupillary control by the oculomotor nucleus is sensitive to glutamate and aspartate but not to several other well known transmitter substances. It, therefore, can serve as a useful site for the evaluation of the nonspecific suppression of neural activity caused by various transmitter antagonists as well as a variety of other excitatory and inhibitory substances.     

Dissociative effects of scopolamine on working memory in healthy young volunteers

Performance on tasks of digit span, mental rotation and immediate free recall of supraspan word lists was measured before and after oral administration of 1.2 mg scopolamine or placebo to healthy young volunteers. Digit span and mental rotation were sensitive to task-specific interference from articulatory suppression and spatial tapping tasks, respectively. Neither task was affected by scopolamine when completed alone or in combination with a secondary task. A concurrent secondary task reduced immediate free recall in a nonspecific fashion (i.e., spatial tapping or articulatory suppression impaired performance equally). Scopolamine significantly reduced the number of words recalled under all conditions. The results are interpreted as evidence for selective impairment of the central executive mechanism by scopolamine without disruption of function in the articulatory loop or visuospatial scratch pad.     

Effects of subchronic exposure to toluene on working and reference memory in rats

Rats that had inhaled 600 ppm of toluene vapor 24 h a day for 50 days after weaning at 3 weeks of age were trained in a radial-arm maze with a 4-out-of-8 baiting procedure, and their performance based upon reference and/or working memory was compared with that of air-exposed control animals during the early stage of acquisition. Pharmacological challenge testing was also conducted after completing a total of 48 training sessions; the effects of scopolamine and methylscopolamine on the maze performance were measured after acute IP administration to determine the long-lasting effects of toluene exposure. During the acquisition stage, toluene-exposed rats made a significantly smaller number of reference memory errors (entries into “never-baited” arms) and total arm entries than the control rats. No significant effects of exposure were observed for working memory errors (reentries into “already-entered” arms). During the pharmacological challenge testing, only scopolamine increased both types of errors significantly. No significant differences due to toluene exposure were revealed.     

Assessment of working memory in rats using spatial alternation behavior with variable retention intervals: effects of fixed-ratio size and scopolamine

The effects of fixed-ratio (FR) size, scopolamine, and the interactions between FR size and scopolamine were investigated in male F344 rats on working memory as assessed by spatial alternation behavior maintained under FR schedules of food presentation where the interval between trials was varied among values of 2, 4, 8, 16, and 32 s within each session. The magnitude of the FR size on the correct and incorrect levers was varied systematically from 1 response to 2, 4, 8, or 16 responses in order to determine whether the FR size influenced either the percentage of correct responding, rates of responding, or both. Under the primary baseline condition, that is when the FR size on both the correct and incorrect levers was one response (designated FR1 FR1), the percentage of correct responses decreased with increasing retention interval duration. Increasing the FR size on the correct lever produced FR-dependent increases in the percentage of correct responding as well as in rates of responding. Increasing the FR size on the incorrect lever produced FR-dependent decreases in correct responding, but had little effect on rates of responding. Dose-effect curves for scopolamine were determined on performance maintained under FR values on the correct and incorrect levers, respectively, of FR1 FR1, FR1 FR10, FR10 FR1, and FR10 FR10. In general, scopolamine produced dose-related decreases in the percentage of correct responding, although the magnitude of the effects of scopolamine varied not only with dose, but also with the length of the retention interval and with changes in FR size. Rates of responding during trials were dose-dependently decreased by scopolamine under all schedule parameters. The present results are consistent with the interpretation that scopolamine can selectively impair time-dependent memory processes such as working memory, but also can impair time-independent variables which affect performance, dependent on dose and schedule maintaining the behavior.     

Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats

RATIONALE: Rolipram, a selective inhibitor of cyclic AMP-specific phosphodiesterase (PDE4), has been shown to enhance scopolamine-induced impairment of working memory. However, its effect on reference memory, which appears to be related to the level of cyclic AMP (cAMP), has not been investigated yet; in addition, the mechanism involved in its effects on memory remains to be elucidated. OBJECTIVES: To investigate the effects of rolipram on working and reference memories impaired by scopolamine and the involvement of cAMP. METHODS: By administration (IP) of rolipram and forskolin, an activator of adenylyl cyclase (AC), the effects of both drugs on the number of correct choices and errors in experiment 1 and, the frequency of both working memory errors and reference memory errors in experiment 2 were observed in two eight-arm radial maze tasks in rats. RESULTS: In experiment 1, rolipram (0.01-1.0 mg/kg) attenuated the scopolamine-induced (0.5 mg/kg) increase in the total number of errors in dose- and time-dependent manners. The minimum effective dose of rolipram was 0.05 mg/kg and the effects lasted nearly 60 min. By contrast, forskolin (1.0-10.0 mg/kg) failed significantly to affect any of the above indices altered by scopolamine. In experiment 2, rolipram (0.05 and 0.1 mg/kg) decreased the frequencies of both working and reference memory errors that were elevated by scopolamine. Forskolin did not alter either type of error at a dose that increased the exploration time. CONCLUSION: Rolipram may exert its effects of reversing both working and reference memory impairments via increased cyclic AMP concentrations in certain signal transduction pathways, rather than by a generalized increase in cAMP.     

Evidence for the modality independence of the genetic epistasis between the dopaminergic and cholinergic system on working memory capacity

Working memory (WM) is fractionated into systems for visuospatial and phonological information. Recently, it has been shown that the dopamine d2 receptor gene DRD2 and CHRNA4, the gene coding for the nicotinic acetylcholine receptor's alpha4 subunit, interact epistatically on visuospatial WM capacity. In the present study, we show a similar interaction on phonological WM capacity in N = 137 healthy subjects genotyped for two single nucleotide polymorphisms (DRD2 rs6277 and CHRNA4 rs1044396). Given the functional independence of the two systems we hypothesize that the genetic interaction targets the central executive which is the common control process for both systems.     

Effects of pesticides and drugs on working memory in rats: continuous non-match

Effects of four pesticides (carbaryl, propoxur, chlordimeform, and deltamethrin) and two reference drugs, physostigmine and chlordiazepoxide, were measured on the performance of rats trained on a continuous non-match (CNM) delayed comparison, working memory procedure. These same compounds were also tested in analogous, large and small stimulus difference discrimination (i.e., non working-memory) procedures. The effects of the pesticides and physostigmine on CNM performance were qualitatively similar, and also similar to their effects on discrimination performance. As dosage of these compounds increased, only small effects on accuracy were observed, followed at still larger doses by an abrupt and non-selective decrease in all responding. The pesticides and physostigmine did not selectively affect working memory: the magnitude of their effects did not increase with intertrial interval, and the compounds were equally effective in disrupting discrimination and CNM performance. Effects of chlordiazepoxide on performance in the CNM and discrimination control procedures differed qualitatively from those of the pesticides and physostigmine.     

Ameliorative effects of histamine on 7-chlorokynurenic acid-induced spatial memory deficits in rats

Rationale. Histamine plays an important role in modulating acquisition and retention in learning and memory process in experimental animals. Objectives. We examined the effects of polyamine and histamine on the N-methyl-d-aspartate (NMDA) receptor glycine site antagonist 7-chlorokynurenic acid-induced spatial memory deficits in radial maze performance in rats. Method. Effects of histamine (0.5 or 1 nmol/site intracerebroventricularly), spermidine (1 nmol/site, intracerebroventricularly) and spermine (1 nmol/site, intracerebroventricularly) on spatial memory deficit in 9-week-old-male Wistar rats were observed. Both reference and working memory errors occurred in radial maze performance in rats, following intracerebroventricular injection of 7-chlorokynurenic acid (10 nmol/site). Results. Spermidine (1 nmol/site, intracerebroventricularly) or spermine (1 nmol/site, intracerebroventricularly) antagonized 7-chlorokynurenic acid-induced deficits on working memory but not on reference memory errors. Intracerebroventricular histamine (0.5 or 1 nmol/site) or thioperamide (100 nmol/site) also ameliorated 7-chlorokynurenic acid-induced working memory deficits. To determine whether the effects of histamine involve histamine receptors, the effects of some methylhistamines were examined. The effects of R-α-methylhistamine on radial maze performance were mimicked by histamine. N^α-methylhistamine had no effect on 7-chlorokynurenic acid-induced memory deficits, whereas 1-methylhistamine, but not 3-methylhistamine reversed 7-chlorokynurenic acid-induced working memory deficits. Conclusion. These results suggest that the amelioration of 7-chlorokynurenic acid-induced working memory deficits by histamine may involve a direct action of histamine at the polyamine sites on NMDA receptors. Electronic Publication